Treatment of autism with cannabidiol

ABSTRACT

The present technology relates to a method of treating one or more behavioral symptoms of Autism Spectrum Disorder (ASD) in a subject by transdermally administering an effective amount of cannabidiol (CBD) to the subject wherein one or more behavioral symptoms of ASD are treated in the subject.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to United Statesprovisional application no. 62/564,834 filed Sep. 28, 2017 and U.S.provisional application No. 62/632,532 filed Feb. 20, 2018. The contentsof each of which are hereby incorporated herein in their entirety.

FIELD OF THE TECHNOLOGY

The present disclosure relates to methods of treating one or morebehavioral symptoms of Fragile X Syndrome in a subject by transdermallyadministering an effective amount of cannabidiol (CBD) to the subjectwherein one or more behavioral symptoms of Fragile X Syndrome aretreated in the subject.

BACKGROUND

Cannabinoids are a class of chemical compounds found in the Cannabisplant. The two primary cannabinoids contained in Cannabis arecannabidiol, or CBD, and Δ9-tetrahydrocannabinol, or THC. CBD lacks thepsychoactive effects of THC. Studies have shown that CBD can be used totreat disorders such as epilepsy, arthritis, and cancer.

FXS is the most common inherited intellectual disability in males and asignificant cause of intellectual disability in females. It is caused bya mutation in the Fragile X Mental Retardation 1 (FMR1) gene located onthe X chromosome and leads to dysregulation of the endocannabinoidsystem including reductions in endogenous cannabinoids (2-AG andanandamide [AEA]). The disorder negatively affects synaptic function,plasticity and neuronal connections, and results in a spectrum ofintellectual disabilities, social anxiety, and memory problems. In theUS, there are about 71,000 patients suffering with FXS.

“Behavior problems are often the most significant concern reported byparents, and high levels of stress and depression and low levels ofquality of life for parents are commonly associated with elevatedproblem behaviors in children.” Wheeler A, Raspa M, Bann C, Bishop E,Hassl D, Sacco H, Bailey D B. 2014. Anxiety attention problems,hyperactivity, and the Aberrant Behavior Checklist in fragile Xsyndrome. Am J Med Genet Part A 164A:141-155, 141.

“As a result, reduction in behavior problems is a primary focus ofongoing clinical trials testing the efficacy of new medications forFXS.” Wheeler at pages 141-142.

The Anxiety, Depression, and Mood Scale (ADAMS) is an instrument that isused by clinicians, doctors, and researchers to assess the level ofanxiety, depression and mood in patients with intellectual disabilities,including FXS. ADAMS consists of questions grouped into five subscales,including (i) general anxiety, (ii) social avoidance, (iii) compulsivebehavior, (iv) manic/hyperactive behavior, and (v) depressed mood. Eachquestion is answered by a clinician/doctor on a four-point scale rangingfrom 0 (“not a problem”) to 3 (“severe problem”). In addition tosubscale scores, the ADAMS yields a total score.

The original Aberrant Behavior Checklist (ABC) was “designed to assessbehavioral concerns of adults within institutional settings.” Wheeler atpage 142. Since then, the original ABC has been adapted to addresspatients who are not institutionalized and specifically to address FXS.Id. The Aberrant Behavior Checklist—FXS Specific (ABC-FXS) scale is usedby clinicians, doctors, and researchers to access certain behaviors inpatients with FXS. The ABC-FXS scale has six subscales including (i)irritability, (ii) hyperactivity, (iii) socially unresponsive/lethargic,(iv) social avoidance, (v) stereotypy, and (vi) in appropriate speech.Similar to ADAMS, the ABC-FXS scale is a four-point Likert-type scaleranging from 0 (not a problem) to 3 (problem is severe).

SUMMARY

The present disclosure relates to a method of treating one or morebehavioral symptoms of Fragile X Syndrome in a subject. The methodincludes transdermally administering an effective amount of cannabidiol(CBD) to the subject wherein one or more behavioral symptoms of FragileX Syndrome are treated in the subject.

In some embodiments, the CBD is (-)- CBD. The effective amount of CBDcan be between about 50 mg to about 500 mg daily. In some embodiments,the effective amount of CBD is initiated at about 50 mg daily andtitrated up to about 500 mg daily. The effective amount of CBD can beinitiated at about 50 mg daily and titrated up to about 250 mg daily. Insome embodiments, the effective amount of CBD is initiated at 250 mgdaily. The effective amount of CBD can be initiated at 500 mg daily. Insome embodiments, the 500 mg daily dose is administered to patients thatweigh greater than 35 kg. The CBD can be administered in a single dailydose or in two daily doses. In some embodiments, the effective amount ofCBD can be 390 mg in divided daily doses.

The CBD can be formulated as a gel or an oil. In some embodiments, theCBD is formulated as a permeation-enhanced gel. The gel can containbetween 1% (wt/wt) CBD to 7.5% (wt/wt) CBD. In some embodiments, the gelcontains 4.2% (wt/wt) CBD. In some embodiments, the gel contains 7.5%(wt/wt) CBD.

In some embodiments, the transdermal preparation can be a cream, a salveor an ointment. The CBD can be delivered by a bandage, pad or patch.

Alleviating one or more behavioral symptoms of Fragile X Syndrome caninclude an improvement in a total score of an Anxiety, Depression andMood Scale (ADAMS). In some embodiments, alleviating one or morebehavioral symptoms of FXS can include improvement in one or moresubscales of ADAMS. Alleviating one or more behavioral symptoms ofFragile X Syndrome can include improvement in one or more measures of anAberrant Behavior Checklist for Fragile X (ABC-FXS).

In some embodiments, the one or more behavioral symptoms is selectedfrom the group consisting of general anxiety, social avoidance,compulsive behavior, manic/hyperactive behavior, irritability, lethargy,stereotypy, and inappropriate speech. The behavioral symptom that isalleviated can be any one of general anxiety, social avoidance,compulsive behavior, manic/hyperactive behavior, irritability, lethargy,stereotypy, inappropriate speech, emotional functioning, psychosocialhealth, written communication, socialization, play and leisure, copingskills, internalizing behavior, externalizing behavior, tantrum/moodliability, hyperactivity/impulsivity, quality of life, or anycombination thereof. In some embodiments, a single symptom isalleviated. In some embodiment, two, three, four, five, six, seven,eight, or nine symptoms are alleviated.

The CBD can be administered transdermally on the subject's upper arm andshoulder. In some embodiments, the CBD is administered transdermally onthe subject's thigh or back.

The CBD can be synthetic CBD. The CBD can be purified CBD. The CBD canbe botanically derived.

Transdermally administering an effective amount of cannabidiol (CBD) canreduce an intensity of at least one adverse event or side effectrelative to orally administering CBD. The at least one adverse event orside effect can be a gastrointestinal (GI) adverse event. The at leastone adverse event or side effect can be liver function. In someembodiments, the at least one adverse event is somnolence. In someembodiments, the frequency and intensity of somnolence is reduced as anadverse event.

In another aspect, a method is provided to treat one or more behavioralsymptoms of an autism spectrum disorder (ASD) in a subject bytransdermally administering an effective amount of CBD to the subjectwherein the one or more behavioral symptoms of ASD are treated in thesubject.

ASD is a behavioral diagnosis having a range of symptoms that aregenerally characterized by an impaired ability to communicate andinteract socially with other people.

The one or more behavioral symptoms of ASD that can be treated include,for example, social avoidance, general anxiety, hyperactivity, depressedmood and compulsive behavior. Alleviating one or more behavioralsymptoms of ASD can include an improvement in a total score of anAnxiety, Depression and Mood Scale (ADAMS). In some embodiments,alleviating one or more behavioral symptoms of ASD can includeimprovement in one or more subscales of ADAMS.

In some embodiments, the CBD is (-)- CBD. The effective amount of CBDcan be between about 50 mg to about 500 mg daily. In some embodiments,the effective amount of CBD is initiated at about 50 mg daily andtitrated up to about 500 mg daily. The effective amount of CBD can beinitiated at about 50 mg daily and titrated up to about 250 mg daily. Insome embodiments, the effective amount of CBD is initiated at 250 mgdaily. The effective amount of CBD can be initiated at 500 mg daily. Insome embodiments, the 500 mg daily dose is administered to patients thatweigh greater than 35 kg. The CBD can be administered in a single dailydose or in two daily doses. In some embodiments, the effective amount ofCBD can be 390 mg in divided daily doses.

The CBD can be formulated as a gel or an oil. In some embodiments, theCBD is formulated as a permeation-enhanced gel. The gel can containbetween 1% (wt/wt) CBD to 7.5% (wt/wt) CBD. In some embodiments, the gelcontains 4.2% (wt/wt) CBD. In some embodiments, the gel contains 7.5%(wt/wt) CBD.

In some embodiments, the transdermal preparation can be a cream, a salveor an ointment. The CBD can be delivered by a bandage, pad or patch.

Alleviating one or more behavioral symptoms of ASD can include animprovement in a total score of an Anxiety, Depression and Mood Scale(ADAMS). In some embodiments, alleviating one or more behavioralsymptoms of ASD can include improvement in one or more subscales ofADAMS.

In some embodiments, the one or more behavioral symptoms is selectedfrom the group consisting of general anxiety, social avoidance,compulsive behavior, manic/hyperactive behavior. The behavioral symptomthat is alleviated can be any one of general anxiety, social avoidance,compulsive behavior, manic/hyperactive behavior, or any combinationthereof. In some embodiments, a single symptom is alleviated. In someembodiment, two, three, or four behavioral symptoms are alleviated.

The CBD can be administered transdermally on the subject's upper arm andshoulder. In some embodiments, the CBD is administered transdermally onthe subject's thigh or back.

The CBD can be synthetic CBD. The CBD can be purified CBD. The CBD canbe botanically derived.

Transdermally administering an effective amount of cannabidiol (CBD) canreduce an intensity of at least one adverse event or side effectrelative to orally administering CBD. The at least one adverse event orside effect can be a gastrointestinal (GI) adverse event. The at leastone adverse even or side effect can be a liver function adverse event.In some embodiments, the at least one adverse event is somnolence. Insome embodiments, the frequency and intensity of somnolence is reducedas an adverse event.

DETAILED DESCRIPTION

As used herein, the term “treating” or “treatment” refers to mitigating,improving, relieving, or alleviating at least one symptom (such as abehavioral symptom) of a condition, disease or disorder in a subject,such as a human, or the improvement of an ascertainable measurementassociated with a condition, disease or disorder.

As used herein, the term “clinical efficacy” refers to the ability toproduce a desired effect in humans as shown through a Food and DrugAdministration (FDA), or any foreign counterparts, clinical trial.

As used herein, the term “cannabidiol” or “CBD” refers to cannabidiol;cannabidiol prodrugs; pharmaceutically acceptable derivatives ofcannabidiol, including pharmaceutically acceptable salts of cannabidiol,cannabidiol prodrugs, and cannabidiol derivatives. CBD includes,2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediolas well as to pharmaceutically acceptable salts, solvates, metabolites(e.g., cutaneous metabolites), and metabolic precursors thereof. Thesynthesis of CBD is described, for example, in Petilka et al., Helv.Chim. Acta, 52:1102 (1969) and in Mechoulam et al., J. Am. Chem. Soc.,87:3273 (1965), which are hereby incorporated by reference.

As used herein, the term “transdermally administering” refers tocontacting the CBD with the patient's or subject's skin under conditionseffective for the CBD to penetrate the skin.

Fragile X Syndrome (FXS) is a genetic condition that causes intellectualdisability, behavioral and learning challenges and various physicalcharacteristics. FXS affects 1 in 4,000 males and 1 in 8,000 females.Patients with FXS can exhibit one or more characteristics of ASD.

The present disclosure relates to a method of treating one or morebehavioral symptoms of Fragile X Syndrome in a subject by transdermallyadministering an effective amount of cannabidiol (CBD) to the subjectwherein one or more behavioral symptoms of Fragile X Syndrome aretreated in the subject.

Clinical and preclinical data support the potential for CBD in treatingepilepsy, arthritis, cancer, and Fragile X Syndrome. Therapeuticmedicines have been developed that utilize innovative transdermaltechnologies to allow for sustained and controlled delivery oftherapeutic levels of CBD. Transdermal delivery of cannabinoids (e.g.,CBD) has benefits over oral dosing because it allows the drug to beabsorbed through the skin directly into the bloodstream. This avoidsfirst-pass liver metabolism, potentially enabling lower dosage levels ofactive pharmaceutical ingredients with a higher bioavailability andimproved safety profile. Transdermal delivery also avoids thegastrointestinal tract, lessening the opportunity for GI related adverseevents and the potential degradation of CBD by gastric acid into THC,which can be associated with unwanted psychoactive effects. Moreover,transdermal delivery of CBD reduces the intensity and frequency ofsomnolence adverse events, which are typically present in oral dosing ofCBD. Transdermal delivery of CBD can avoid liver function adverseevents, which are typically present in oral dosing of CBD. In someembodiments, transdermally administering an effective amount of CBDreduces an intensity of at least one adverse event by about 15% to about95% relative to orally administering CBD.

The CBD can be in a gel form and can be pharmaceutically-produced as aclear, permeation-enhanced gel that is designed to provide controlleddrug delivery transdermally with once- or twice-daily dosing. The CBDgel can between 1% (wt/wt) CBD to 7.5% (wt/wt) CBD. The CBD gel canhave, for example, 4.2% (wt/wt) CBD or 7.5% (wt/wt) CBD). The CBD gelcan be applied topically by the patient or caregiver to the patient'supper arm and shoulder, back, thigh, or any combination thereof.

The CBD gel can include diluents and carriers as well as otherconventional excipients, such as wetting agents, preservatives, andsuspending and dispersing agents.

The CBD gel can include a solubilizing agent, a permeation enhancer, asolubilizer, antioxidant, bulking agent, thickening agent, and/or a pHmodifier. The composition of the CBD gel can be, for example, a.cannabidiol present in an amount of about 0.1% to about 20% (wt/wt) ofthe composition; b. a lower alcohol having between 1 and 6 carbon atomspresent in an amount of about 15% to about 95% (wt/wt) of thecomposition; c. a first penetration enhancer present in an amount ofabout 0.1% to about 20% (wt/wt) of the composition; and d. water in aquantity sufficient for the composition to total 100% (wt/wt). Otherformulations of the CBD gel can be found in International PublicationNo. WO 2010/127033, the entire contents of which are incorporated hereinby reference.

EXAMPLES Example 1: Study Design and Data

A total of 20 patients (mean age=10.8, SD=4.0) were enrolled in a12-week study. Eighteen patients (14 males, 4 females) aged 6 to 17years of age (mean=11.2 SD=3.96) with Fragile X as confirmed bymolecular documentation of FMR1 full mutation completed the open labelFAB-C study through week 12. CBD gel was added on to other medicationsbeing administered. The first six weeks of the study were designed totitrate dosing in patients.

Dosing was initiated at 50 mg CBD daily and could be increased to 250 mgCBD daily. Weeks 7 through 12 of the study comprised the maintenanceperiod where patients were treated at the dose established by week sixat a maximum of 250 mg CBD daily. At the completion of the study,patients could enter an open label extension study for up to 12 months.

The primary endpoint for the trial was the change in the total score ofthe Anxiety, Depression, and Mood Scale (ADAMS) from baseline to week12. The ADAMS is a 28-item scale designed to assess general anxiety,social avoidance, compulsive behavior, manic/hyperactive behavior, anddepressed mood. It has been validated in patients with FXS.

Results for the primary endpoint are summarized in Table 1, detailingefficacy scales mean (standard deviation) values at baseline and week 12for the ADAMS Total Score.

TABLE 1 Week Percent Change Baseline 12 from Baseline (n = 18) (n = 18)(%; n = 18) p Value* ADAMS: 32.1 18.1 −43.61 p < 0.0001 Total Score(14.36) (8.32) *P-values are presented for the comparison of the Week 12value to the Baseline value for the total score and each subscale, amongthose who completed the study (n = 18).

The subscales of the ADAMS are summarized in Table 2, detailing efficacyscales mean (standard deviation) values at baseline and week 12.

TABLE 2 Week Percent Change Baseline 12 from Baseline (n = 18) (n = 18)(%; n = 18) p Value* ADAMS: 8.8 6.1 −30.68 p = 0.0003 Manic/ (3.99)(3.29) Hyperactive Behavior Subscale ADAMS: 2.9 2.0 −31.03 p = 0.1417Depressed Mood (3.94) (2.35) Subscale ADAMS: Social 9.9 4.8 −51.52 p =0.0002 Avoidance (5.18) (2.07) Subscale ADAMS: 9.4 4.6 −51.06 p < 0.0001General Anxiety (4.35) (3.35) Subscale ADAMS: 2.7 1.4 −48.15 p = 0.0262Compulsive (2.40) (1.42) Behavior Subscale *P-values are presented forthe comparison of the Week 12 value to the Baseline value for the totalscore and each subscale, among those who completed the study (n = 18).

Compared to the baseline total score, the CBD transdermal gel treatedpatients has a 44% reduction (p<0.0001) in the ADAMS Total Score.Furthermore, the CBD transdermal gel treated patients has statisticallyand clinically significant improvement compared to baseline in all butone of the ADAMS subscales (i.e., manic/hyperactive behavior, socialavoidance, general anxiety, and compulsive behavior) at week 12. Asignificant change was not observed for the depressed mood subscale ofthe ADAMS.

Multiple secondary efficacy endpoints including the Aberrant BehaviorChecklist—FXS Specific (ABC-FXS), the Pediatric Anxiety Rating Scale(PARS-R), Visual Analog Scale (VAS) for Anxiety, Hyperactivity andTantrum/Mood Lability, the Vineland Adaptive Behavior (VLD) III, and thePediatric Quality of Life (PedsQL™). Both the PARS-R and the Vinelandscales are clinician-rated, while the other scales are caregiver-rated.

The primary and secondary endpoints were evaluated prior to andfollowing 12 weeks of drug administration. The results of the secondaryendpoints reinforce the results demonstrated in the ADAMS. Consistentwith findings from the ADAMS, patients taking the CBD transdermal geldemonstrated statistically and clinically significant 12-week reductionsin all subscales of the ABC-FXS (i.e., irritability, hyperactivity,socially unresponsive/lethargic, social avoidance, stereotypy, andinappropriate speech), and both total score calculations of the PARS-R(i.e., 5- and 7-item).

Patients also showed significant improvement between Baseline and Week12 scores for all remaining scales except for the Physical Function,School Functioning, and Social Functioning subscales of the PedsQL, aswell as some subscales of the VLD (e.g., communication, daily livingskills). Both the VLD and ADAMS are being administered in the extensionPhase 2 of the trial.

Results from the ABC-FXS are summarized in Table 3, detailing efficacyscales mean (standard deviation) values at baseline and week 12.

TABLE 3 Percent Week Change from Baseline 12 Baseline (n = 18) (n = 18)(%; n = 18) p Value* ABC: Irritability 17.7 10.6 −40.11 p = 0.0096(12.68) (11.03) ABC: Hyperactivity 13.7 9.8 −28.47 p = 0.0237 (9.09)(7.38) ABC: Socially 9.2 4.1 −55.43 p = 0.0034 Unresponsive/Lethargic(6.40) (4.09) ABC: Social 5.1 2.3 −54.90 p = 0.0005 Avoidance (3.46)(2.22) ABC: Stereotypy 8.1 3.2 −60.49 p = 0.0006 (5.91) (3.07) ABC:Inappropriate 5.9 3.5 −40.68 p = 0.0018 Speech (2.30) (2.66) *P-valuesare presented for the comparison of the Week 12 value to the Baseline,among those who completed the study (n = 18).

Results from the PARS-R are summarized in Table 4, detailing efficacyscales mean (standard deviation) values at baseline and week 12.

TABLE 4 Percent Week Change from Baseline 12 Baseline (n = 18) (n = 18)(%; n = 18) p Value* PARS-R—5 Item 15.7 10.6 −32.48 p = 0.0006 (3.88)(3.43) PARS-R—7 Item 21.3 14.4 −32.39 p = 0.0004 (5.55) (4.54) *P-valuesare presented for the comparison of the Week 12 value to the Baselinevalue, among those who completed the study (n = 18).

Results from the VAS for Anxiety, Hyperactivity and Tantrum/MoodLability are summarized in Table 5.

TABLE 5 Percent Week Change from Baseline 12 Baseline (n = 18) (n = 18)(%; n = 18) p Value* VAS— 5.9 3.6 −38.98 p = 0.0002Hyperactivity/Impulsivity (2.43) (2.49) VAS—Tantrum/Mood 4.7 3.2 −31.91p = 0.0023 Liability (2.09) (2.18) VAS—Anxiety 6.0 3.8 −36.67 p = 0.0005(2.05) (1.93) *P-values are presented for the comparison of the Week 12value to the Baseline value, among those who completed the study (n =18).

Results from the PedsQL are summarized in Table 6, detailing efficacyscales mean (standard deviation) values at baseline and week 12.

TABLE 6 Percent Week Change from Baseline 12 Baseline (n = 18) (n = 18)(%; n = 18) p Value* PedsQL: Total Score 57.8 67.7 17.13 p = 0.0100(18.78) (18.27) PedsQL: Physical 67.9 78.0 14.87 p = 0.0606 Functioning(27.36) (22.39) PedsQL: Emotional 64.0 78.3 22.34 p = 0.0394 Functioning(20.72) (16.63) PedsQL: Social 37.3 49.0 31.37 p = 0.0717 Functioning(24.70) (24.35) PedsQL: School 55.7 59.1 6.10 p = 0.3580 Functioning(19.17) (22.47) PedsQL: Psychosocial 52.4 62.2 18.70 p = 0.0408 Health(17.22) (18.91) *P-values are presented for the comparison of the Week12 value to the Baseline value, among those who completed the study (n =18).

Results from the VLD III are summarized in Table 7, detailing efficacyscales mean (standard deviation) values at baseline and week 12.

TABLE 7 Percent Week Change from Baseline 12 Baseline (n = 18) (n = 18)(%; n = 18) p Value* VLD III: Overall 46.1 48.9 6.07 p = 0.0472 AdaptiveBehavior (16.29) (16.49) Composite VLD III: 36.7 39.2 6.81 p = 0.2968Communication (18.52) (20.34) VLD III: 3.9 5.3 35.90 p = 0.0752Communication— (3.43) (4.34) Receptive VLD III: 3.3 3.7 12.12 p = 0.5070Communication— (3.63) (4.07) Expressive VLD III: 4.4 3.8 −13.64 p =0.0293 Communication— (3.81) (3.64) Written VLD III: Daily 52.7 54.63.61 p = 0.3911 Living Skills (21.19) (18.46) VLD III: Daily 5.7 6.28.77 p = 0.3374 Living Skills— (4.26) (4.33) Personal VLD III: Daily 9.69.5 −1.04 p = 0.9395 Living Skills— (3.42) (3.09) Domestic VLD III:Daily 4.6 4.7 2.17 p = 0.5636 Living Skills— (3.09) (2.93) Community VLDIII: 45.9 50.9 10.89 p = 0.0344 Socialization (16.22) (17.83) VLD III:5.3 5.9 11.32 p = 0.2937 Socialization— (3.51) (3.64) InterpersonalRelationships VLD III: 3.4 4.5 32.35 p = 0.0350 Socialization— (2.91)(3.93) Play and Leisure VLD III: 6.6 7.8 18.18 p = 0.0246 Socialization—(2.93) (2.84) Coping Skills VLD III: 19.9 18.7 −6.03 p = 0.0486Maladaptive (1.71) (1.79) Behavior— Internalizing VLD III: 18.7 17.2−8.02 p = 0.0090 Maladaptive (2.42) (2.66) Behavior— Externalizing*P-values are presented for the comparison of the Week 12 value to theBaseline value, among those who completed the study (n = 18).

Among the 18 patients who completed 12 weeks of treatment, averageimprovement in overall anxiety and depression (ADAMS Total Score)reached 44% (p<0.01), with particular benefit observed for the GeneralAnxiety (51%; p<0.01) and Compulsive Behavior subscales (48%; p<0.05).Additionally, improvements as measured by ABCFxs ranging from 28%(Hyperactivity subscale; p0<.05) to 60% (Stereotypy subscale; p0<.01)were observed in aberrant behavior, with the Social Avoidance (p<0.01)and Social Unresponsiveness/Lethargy subscales (p<0.01) each improvingby 55% during the treatment period. Beyond individual symptoms, qualityof life improved by 17% (p=0.01).

The trial successfully met its primary endpoint, achieving a 44%improvement (P<0.0001) in the total ADAMS score at week twelve comparedto baseline. The trial also achieved clinically meaningful improvementsin all measures of the ABC-FXS, which address the key symptoms of FXSincluding irritability, hyperactivity, social unresponsiveness, socialavoidance, stereotypy, and inappropriate speech.

Following the 12-week open-label study, patients were allowed to rollinto a 1-year open-label extension study. 72% (n=13) of the 18 patientswho completed the initial 12-week study rolled into the extension. Whilethe open-label extension is ongoing, some data have been collectedthrough Week 38 (12 weeks in initial study and up to 6 months in theextension study). Results from the extension study demonstrate continuedgains in the two measures collected (ADAMS and ABCFxs). Indeed, thosewho have completed a Week 38 visit (n=4) showed significant gains fromscreening in overall anxiety and depression, with participantsexperiencing an average improvement in the ADAMS total score of 74%.Similar improvement was observed for aberrant behavior, ranging from 75%(Irritability subscale) to 96% (Social Avoidance subscale) and 97%(Socially Unresponsiveness/Lethargy subscale) at Week 38.

The open-label extension continues to be ongoing and data has beencollected through Week 51. The results are summarized in Table 8(ABCFxs) and Table (ADAMS).

TABLE 8 (ABC_(FXS)) Week 12 Week 38 Week 51 Screening Mean Mean MeanWeek (baseline Change Change Change 51 score) (%) (%) (%) P N = 12 N =12 N = 9 N = 9 values Irritability 22.3 51.1 63.7 59.2 0.0007Hyperactivity 16.6 36.7 48.2 40.4 0.0037 Socially 10.8 65.7 83.3 72.20.0035 Unresponsive/ Lethargic Social Avoidance 5.7 57.9 75.4 77.20.0013 Stereotypy 9.7 60.8 73.2 64.9 0.0012 Inappropriate 6.2 56.5 66.156.5 <0.0001 Speech

TABLE 9 (ADAMS) Week 12 Week 38 Week 51 Screening Mean Mean Mean(baseline Change Change Change score) (%) (%) (%) Week 51 N = 12 N = 12N = 12 N = 12 P values Manic/ 8.8 34.1 53.4 45.5 0.0014 HyperactivityDepressed Mood 3.2 43.8 62.5 59.4 0.0032 Social Avoidance 9.9 52.5 61.655.6 0.0004 General Anxiety 9.8 55.1 58.2 58.2 <0.0001 Compulsive 3.250.0 59.4 59.4 0.0213 Behavior Total Score 33.3 48.6 59.2 54.4 <0.0001

CBD gel was well tolerated, with excellent skin tolerability. Onepatient discontinued due to worsening of pre-existing eczema. No otheradverse events led to discontinuation and no adverse events wereconsidered severe. The most common adverse events were mild-moderategastroenteritis (n=6) and upper respiratory tract infection (n=5).However, no patient experienced drug-related GI events during the12-week treatment period and no THC was detected in the plasma.

The clinical results of the trial are significant for the many patientsworldwide with FXS who currently have no approved therapeutic options totreat their symptoms. The data, in particular the improvements inanxiety, social avoidance, and irritability as measured by ADAMS,ABC-FXS and PARS-R, are significant. The CBD gel was very well toleratedin children and adolescents with FXS.

Example 2: Patient Monograph as Reported by Parent

This is the report regarding a 7 year old child participating in theabove study and continuing on an extension study—as reported by thecaregiver. The caregiver's son has full mutation Fragile X Syndrome. Heis reported, prior to the trial, to be non-verbal, severelyintellectually impaired, visually impaired, still in need of diapers andas having very severe GI issues requiring that he is fed by a feedingtube every two hours. Prior to the beginning the trial the child neverever made eye contact, rarely could leave his home without severeemotional distress, did not initiate any form of communication at all,intensely disliked being touched including by his parents, would notallow even family to sit next to him, and would leave the room if anyonewalked into it.

Within the first two weeks of the trial, the patient began to make moreeye contact, initiated physical contact with his family, e.g., grabbinghis mother's hand, initiated emotional contact with his family includingseeking to be in the same room with his family, and exhibited improvedability to leave the house, even to the extent the family could taketheir very first vacation together.

After the end of the initial trial and a few weeks into the extendedtrial, the caregiver recorded another big change in the patient. Hestarted greeting his family, initiated and engaged in games that aremore complex, exhibited/shared preferences for things instead of onlyrejecting all choices, and he began acknowledging the family pets. Healso allowed his doctor to touch him and hold onto him without gettingdistressed. Patient began to use body signing (sign language) for thevery first time. Patient communicated very clearly that he missed hismother for the very first time and was eager to be embraced and held byhis mother.

Patient is reported to be happier, more relaxed, able to engage theworld in ways he could not before, and able to learn new skills that hecould not previously. His teachers, therapists and aids have alsoremarked in the changes in the patient.

1-31. (canceled)
 32. A method of treating a human suffering from anautism spectrum disorder comprising: transdermally administering via agel or cream a therapeutically effective amount of purified cannabidiolto the human suffering from the autism spectrum disorder to effectivelytreat the autism spectrum disorder in the human in need thereof, whereinthe gel or cream is administered to the upper arm.
 33. The method ofclaim 32, wherein the cannabidiol is (-)-cannabidiol.
 34. The method ofclaim 32, wherein the therapeutically effective amount of cannabidiol is250 mg total daily.
 35. The method of claim 32, wherein thetherapeutically effective amount of cannabidiol is 500 mg total daily.36. The method of claim 32, wherein the cannabidiol is formulated as apermeation-enhanced gel.
 37. The method of claim 32, wherein thecannabidiol is administered in a single-daily dose.
 38. The method ofclaim 32, wherein the cannabidiol is administered in two daily doses.39. The method of claim 32, wherein the therapeutically effective amountof cannabidiol is between about 50 mg to 500 mg total daily.